The intent of the work presented in this proposal is to address the worldwide health problem brought on by the spread of chloroquine-resistant malaria. An orally available and inexpensive class of replacement drugs termed "reversed chloroquines" (RCQs) is proposed which are expected to act against both chloroquine- resistant and chloroquine-sensitive malaria. Specifically, the following goals are proposed for this research: Goal 1. To understand how to optimize structural features in the next-generation set of RCQ molecules. This will be accomplished by producing a panel of varied RCQ structures, and then testing them against chloroquine-sensitive and chloroquine-resistant malaria, as well as for solubility, central nervous system receptor activity, and cytotoxicity. The most promising candidates will then be evaluated as orally available drugs against malaria in mice. Goal 2. To assess the RCQ mode(s) of action. This will be accomplished by design and testing of RCQ variants which have strategic alterations to the RCQ structures to probe for specific aspects of their action against malaria, by spectroscopic investigations of interactions between heme and RCQs, by inhibition of hemozoin formation, and by measuring the effects on CQ accumulation/efflux of co-administered CQ. After having established the feasibility of the RCQ molecular design, as well providing fundamental understanding of correlations between molecular features and efficacy of RCQs against malaria, the RCQ structures will be "tuned" in order to optimize practical aspects of their use in humans. Although we are directing this study specifically against Plasmodium falciparum, the most problematic human malaria variant, RCQs should also be effective against red blood cell stages of the other human malarias. Malaria is a disease that infects almost half a billion people annually, and kills between one and three million, most of whom are either children or pregnant women. The impact of malaria is increasing, partly because the parasite that causes malaria has evolved into strains that are resistant to our best drugs for treating the disease. This work outlined for this project is to produce and test novel drugs that are designed to circumvent this resistance, as well as to elucidate the way(s) in which these novel drugs work. [unreadable] [unreadable] [unreadable]